A Large Population Histology Study Showing the Lack of Association between ALT Elevation and Significant Fibrosis in Chronic Hepatitis B

OBJECTIVE: We determined the association between various clinical parameters and significant liver injury in both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients. METHODS: From 1994 to 2008, liver biopsy was performed on 319 treatment-naive CHB patients. Histologic assessment was based on the Knodell histologic activity index for necroinflammation and the Ishak fibrosis staging for fibrosis. RESULTS: 211 HBeAg-positive and 108 HBeAg-negative patients were recruited, with a median age of 31 and 46 years respectively. 9 out of 40 (22.5%) HBeAg-positive patients with normal ALT had significant histologic abnormalities (necroinflammation grading >/= 7 or fibrosis score >/= 3). There was a significant difference in fibrosis scores among HBeAg-positive patients with an ALT level within the Prati criteria (30 U/L for men, 19 U/L for women) and patients with a normal ALT but exceeding the Prati criteria (p = 0.024). Age, aspartate aminotransferase and platelet count were independent predictors of significant fibrosis in HBeAg-positive patients with an elevated ALT by multivariate analysis (p = 0.007, 0.047 and 0.045 respectively). HBV DNA and platelet count were predictors of significant fibrosis in HBeAg-negative disease (p = 0.020 and 0.015 respectively). An elevated ALT was not predictive of significant fibrosis for HBeAg-positive (p = 0.345) and -negative (p = 0.544) disease. There was no significant difference in fibrosis staging among ALT 1-2 x upper limit of normal (ULN) and > x 2 ULN for both HBeAg-positive (p = 0.098) and -negative (p = 0.838) disease. CONCLUSION: An elevated ALT does not accurately predict significant liver injury. Decisions on commencing antiviral therapy should not be heavily based on a particular ALT threshold.published_or_final_versio

High versus standard doses interferon-alpha in the treatment of naïve chronic hepatitis C patients in Taiwan: a 10-year cohort study

BACKGROUND: Interferon-alpha monotherapy is effective in less than one-third patients with chronic hepatitis C. The dose-effect, tolerability and durability of interferon-alpha treatment and its long-term effect on the prevention of cirrhosis and hepatocellular carcinoma in naïve Taiwanese patients with chronic hepatitis C have not been well investigated. We conducted the present cohort study treated with high and standard interferon-alpha to illustrate the issues. METHODS: We performed a long-term virologic and histological follow-up of 214 chronic hepatitis C patients treated with interferon-alpha, 3 million units (3-MU, n = 80) or 6-MU (n = 134) thrice weekly for 24 weeks, in Taiwan between 1992 and 2001. RESULTS: There was no difference in the incidence of discontinuation between 3-MU and 6-MU groups (4/80, 5.0% versus 10/134. 7.5%). The 6-MU group had similar incidence of adverse events with the 3-MU group, except that 6-MU group had significantly higher incidence of psychological manifestations, mainly presented as irritability. The rates of sustained virological response (SVR) were significantly higher in 6-MU regimen (37.1%) than in 3-MU regimen (23.7%, p < 0.05) in per protocol analysis. Based on multivariate analysis, baseline viral load was strongly associated with SVR, followed by hepatitis C virus genotype, interferon-alpha regimen, and liver fibrosis. A histological improvement in necroinflammatory activity, but not in fibrosis was observed in the follow-up biopsy performed 0.5–5.5 years (mean: 1.9 years, n = 51) after end-of-treatment. Among patients without SVR, there was more activity improvement in 6-MU group. The durability of SVR was 100% (18/18) and 97.8% (45/46) for 3-MU and 6-MU group, respectively, in a mean follow-up period of 6.81 years (5.25–9.18 years). For 163 baseline non-cirrhotic patients, 9 of 84 (10.7%) non-responders and 3 of 79 (3.8%) sustained responders progressed to cirrhosis during a mean follow-up period of 5.52 and 5.74 years, respectively (p = 0.067, Kaplan-Meier survival analysis, log-rank test). For all 200 patients, hepatocellular carcinoma was detected in 12 of 113 (10.6%) non-responders and one of 87 (1.1%) sustained responders during a mean follow-up period of 5.67 and 5.73 years, respectively (p < 0.01, Kaplan-Meier survival analysis, log-rank test). CONCLUSION: We confirm the dose effect of interferon-alpha in chronic hepatitis C. Six-MU regimen had better efficacy than 3-MU regimen in virologic and histological responses. Both regimens had good tolerability and durability in Taiwan. Sustained response could reduce the incidence of cirrhotic change and hepatocarcinogenesis

Soluble Serum CD81 Is Elevated in Patients with Chronic Hepatitis C and Correlates with Alanine Aminotransferase Serum Activity

Aim: Cellular CD81 is a well characterized hepatitis C virus (HCV) entry factor, while the relevance of soluble exosomal CD81 in HCV pathogenesis is poorly defined. We performed a case-control study to investigate whether soluble CD81 in the exosomal serum fraction is associated with HCV replication and inflammatory activity. Patients and Methods: Four cohorts were investigated, patients with chronic hepatitis C (n = 37), patients with chronic HCV infection and persistently normal ALT levels (n = 24), patients with long term sustained virologic response (SVR, n = 7), and healthy volunteers (n = 23). Concentration of soluble CD81 was assessed semi-quantitatively after differential centrifugation ranging from 200 g to 100,000 g in the fifth centrifugation fraction by immunoblotting and densitometry. Results: Soluble CD81 was increased in patients with chronic hepatitis C compared to healthy subjects (p = 0.03) and cured patients (p = 0.017). Patients with chronic HCV infection and persistently normal ALT levels and patients with long term SVR had similar soluble CD81 levels as healthy controls (p>0.2). Overall, soluble CD81 levels were associated with ALT levels (r = 0.334, p = 0.016) and severe liver fibrosis (p = 0.027). Conclusion: CD81 is increased in the exosomal serum fraction in patients with chronic hepatitis C and appears to be associated with inflammatory activity and severity of fibrosis